Pulmonary fibrosis (PF) is a complicated, chronic illness characterized by abnormal formation of fiberlike scar tissue in the lungs. Most patients with PF first have alveolitis, or inflammation of the lung, which drives the scarring process. If the disease progresses, the lungs eventually thicken and become stiff, which prevents oxygen from getting from the air sacs into nearby blood vessels that deliver oxygen to the body, thus making it more difficult for the person to breathe.
PF affects each person differently, and progresses at varying rates. Generally, the patient's breathlessness becomes worse over time, and daily activities such as walking, climbing stairs, etc. become more difficult. As the disease advances, the patient may require supplemental oxygen to meet the demands of the body. PF causes hypoxemia, or a lack of oxygen in the blood. This condition may lead to high blood pressure in the lungs (pulmonary hypertension) and put a strain on the heart that can lead to heart dysfunction. PF has also been associated with heart attack, respiratory failure, stroke, pulmonary embolism, and lung infection. In some cases PF can even be fatal.
There are many known causes of PF, including occupational and environmental exposures, sarcoidosis, medications, radiation, connective tissue or collagen diseases such as rheumatoid arthritis and systemic sclerosis, and genetic/familial causes (less common). When all known causes of PF have been excluded, the condition is labeled as idiopathic pulmonary fibrosis (IPF). No matter what the cause, in each case of PF the lung is reacting to some insult by developing inflammation which leads to an exaggerated or uncontrolled healing response that, over time, produces fibrous scar tissue. The histological features of pulmonary fibrosis in human and animal studies include inflammatory cell recruitment, fibroblast proliferation and collagen synthesis. A number of studies concerning the pathogenesis of pulmonary fibrosis have focused on the role of inflammatory cells, especially alveolar macrophages, in the fibrotic process.
Current treatments for PF focus on improving symptoms and slowing progression of the disease. These include administration of corticosteroids to reduce inflammation, which are often used in combination with a drug to suppress the body's immune response, such as azathioprine or cyclophosphamide. Unfortunately, this treatment approach improves symptoms and/or improves the life span only some of the time. These drugs can also cause numerous side effects, some of which are severe. Interferon gamma-Ib is a new drug shown to be superior to corticosteroids in preliminary studies. However, its current cost (approximately $100,000/year) is prohibitive for most patients.
In advanced cases of PF, doctors may consider lung transplantation. This procedure is most often performed in patients under 60 years of age whose PF has been unresponsive to other treatments. However, lung transplantation is extremely invasive and expensive, and often requires patients to wait months to years until matching organs become available. Further, many patients are ineligible for transplantation.
There is therefore a need in the art for a new method and means of treating PF that overcomes at least some of the disadvantages associated with current treatments.
As noted above, certain medications are associated with the development of pulmonary fibrosis, including nitrofurantoin, amiodarone, and the chemotherapeutic agents bleomycin, cyclophosphamide, and methotrexate. Bleomycin is a group of glycopeptides isolated from Streptomyces verticillus. Although it is an effective antineoplastic agent, bleomycin-induced pulmonary fibrosis can become fatal and therefore limits the usefulness of the drug. Bleomycin has a differential effect on pulmonary fibrosis. Evidence suggests that there is an individual susceptibility in pulmonary fibrosis, and genetic factors are implicated in the pathogenesis of fibrosis to explain variation in susceptibility. Bleomycin induces inflammatory cells from human and animal lung to secrete multifunctional cytokines, such as TNF-α, IL-1β, IL-8, and TGF-β.
The mechanism of bleomycin-induced cytokine production is not well understood. The cytotoxic effect of bleomycin is believed to be related to DNA damage that is characterized by the appearance of DNA damage-inducible proteins and apoptosis. There is also increased activity of NF-kB, which may result from the increase of reactive oxygen species by bleomycin. NF-kB is a transcriptional factor that regulates the expression of many cytokine genes. Among these, TGF-β is considered to be an important cytokine related to fibroblast proliferation and collagen synthesis and TNF-α is considered to be a central mediator in bleomycin-induced pulmonary fibrosis. TNF-α receptor knockout mice have been shown to be protected from pulmonary injury following exposure to bleomycin.
Pulmonary surfactant is essential for normal lung function. The primary function of pulmonary surfactant is to reduce surface tension at the air-liquid interface of the alveolus, which in turn prevents lung collapse at low lung volumes.
Surfactant protein A (SP-A), in addition to surfactant-related function, plays a role in local host defense and regulation of inflammatory processes in the lung. Moreover, SP-A regulates cytokine expression by alveolar macrophages (i.e. IL-1, TNF-α etc.) and expression of SP-A itself is regulated by cytokines (such as IFN-γ). SP-A also stimulates fibroblasts to produce collagen, and may affect cytokine expression by lung fibroblasts.
SP-A is a collagenous C-type lectin or collectin and its carbohydrate recognition domain (CRD) is involved in binding SP-A to pathogens and promoting phagocytosis of these pathogens by the macrophages. In the macrophage-like THP-1 cell line, human SP-A stimulates production of TNF-α, IL-1β, IL-8, and IL-6 in a dose- and a time-dependent manner. SP-A-enhanced TNF-α production appears to involve NF-kB activation. SP-A also enhances immune cell proliferation and increases expression of some cell surface proteins. In addition, SP-A knockout mice show an increased susceptibility to infection. A recent in vivo study suggests a role for SP-A in neutrophil recruitment into the lungs of preterm lambs.
Surfactant lipids (surfactant TA) can modulate adherence and superoxide production of neutrophils. Surfactant lipids inhibit several SP-A regulated immune cell functions, including stimulation of macrophages. Surfactant lipids and SP-A may be counterregulatory and changes in the relative amounts of surfactant lipids to SP-A may be important in determining the immune status of the lung. Although most of SP-A in the normal alveolar space is thought to be lipid-associated, “lipid-free” SP-A could increase if the balance between SP-A and surfactant lipid was altered under certain conditions.
The present inventors have now found that SP-A plays a role in bleomycin-induced fibrosis, by affecting cytokine expression and/or collagen production. It has further been discovered that “lipid-free” SP-A, the result of an imbalance of SP-A and surfactant lipids following bleomycin treatment, may enhance the effect of bleomycin on proinflammatory cytokine production, and may be partly responsible for bleomycin-induced pulmonary fibrosis. Based on these findings, the present inventors have now determined that the administration of surfactant lipids is effective in suppressing the pulmonary inflammatory processes induced by bleomycin or other causative agents, thereby preventing PF.
Infectious vaginitis is the most common reason that women present for healthcare with a gynecologic condition, accounting for ten million visits per year in the United States. The impact of vaginitis on health outcomes is large, and affects women of every reproductive age, ranging from major pregnancy complications and preterm labor, to infertility, post-operative infection, and increases susceptibility to sexually transmitted diseases (STDs).
There are estimated to be six million cases of bacterial vaginosis (BV) per year in the United States, half of which are without symptoms. Characterized by a shift in vaginal microbes toward a predominance of anaerobic species, BV is the most frequently encountered form of vaginitis. The substantial impact of vaginitis on several important women's health disorders is increasingly coming to light. For example, in both symptomatic and asymptomatic forms, vaginitis has been shown in multiple studies to be highly associated with preterm birth. Importantly, while standard treatment in pregnancy will resolve the vaginitis, the incidence of preterm birth is not reduced by vaginitis detection and treatment protocols carried out in an otherwise low risk population. While the activation of the vaginal immune response has been thought to be a critical determinant of adverse outcomes in women with BV, the mechanism by which vaginal immunity becomes active has been previously unknown.
The present inventors have also surprisingly discovered that SP-A is expressed in the vaginal mucosa and is present in vaginal lavage find. Based upon this finding, the inventors speculate that administration of surfactant lipids is also effective in decreasing proinflammatory cytokines in women, thereby preventing or reducing the symptoms of vaginitis, and preventing complications resulting from vaginitis, such as preterm labor.
It is therefore a primary objective of the present invention to provide a means of preventing and/or treating pulmonary fibrosis.
It is another objective of the present invention to provide a means of preventing and/or treating bleomycin-induced pulmonary fibrosis.
It is a further objective of the present invention to provide a means of preventing and/or treating pulmonary fibrosis through the administration of surfactant lipids.
It is still a further objective of the present invention to provide a means of preventing and/or treating pulmonary fibrosis that is more effective than previously available treatments for PF.
It is a yet a further objective of the present invention to provide a means of preventing and/or treating pulmonary fibrosis that has a lesser degree of side effects than previously available treatments for PF.
It is a further objective of the present invention to provide a method and means of preventing and/or treating vaginitis.
It is still a further objective to provide a method and means of preventing and/or treating vaginitis through the administration of surfactant lipids.
It is a further objective of the present invention to provide a method and means of preventing complications that arise from vaginitis, such as preterm labor, infertility, post-operative infection, and STDs.
These and other objectives will become clear from the foregoing detailed description.